LILRB1-directed CAR-T cells for the treatment of hematological malignancies
CD19 CAR-T cells have established a new standard for relapsed/refractory B-cell malignancies. However, the treatment fails in 50% of patients, often due to CD19 antigen loss. Alternative immunotherapies targeting other antigens are being tested but show limited efficacy, especially in cases of lineage switching or loss of B-cell phenotype, highlighting the need for novel targets. Herein, we identified leukocyte-immunoglobulin-like-receptor-B1 (LILRB1, CD85j) as a novel target for CAR-T cells through cell surface proteomics on patient-derived samples of high-risk B-cell acute lymphoblastic leukemia (B-ALL). LILRB1, an immune inhibitory receptor, is normally expressed only on monocytes and B-cells. We observed stable LILRB1 expression in B-ALL and B-cell non-Hodgkin lymphoma (B-NHL), even after CD20/CD19-based immunotherapies. LILRB1 CAR-T cells showed antigen-specific antitumor activity in vitro against B-ALL/B-NHL cells, including those resistant to CD19 CAR-T-cells, and in vivo in B-ALL xenografts. Additionally, we identified LILRB1 in monocytic acute myeloid leukemia (AML) and demonstrated LILRB1 CAR-T cell cytotoxicity against AML cell lines in vitro and in vivo. These findings establish LILRB1 as a novel target for cancer immunotherapy and show evidence for the preclinical efficacy of LILRB1 CAR-T cells against haematological malignancies, including cases resistant to previous lines of immunotherapy, thus holding promise for further clinical development.
Authors
- Agata Malinowska (ORCID: https://orcid.org/0000-0001-6599-901X)
- Pablo Menéndez (ORCID: https://orcid.org/0000-0001-9372-1007)
- Ewa Lech‐Marańda (ORCID: https://orcid.org/0000-0001-9592-0851)
- Sébastien Wälchli (ORCID: https://orcid.org/0000-0001-5869-1746)
- Alicia Villatoro (ORCID: https://orcid.org/0000-0002-8027-0021)
- Łukasz Słota (ORCID: https://orcid.org/0000-0003-1342-3013)
- Bianka Świderska (ORCID: https://orcid.org/0000-0002-9373-4008)
- Łukasz Sędek (ORCID: https://orcid.org/0000-0001-9384-914X)
- Monika Pępek (ORCID: https://orcid.org/0000-0003-3506-8040)
- Agnieszka Krzywdzińska (ORCID: https://orcid.org/0000-0002-7647-3336)
- Christopher Forcados (ORCID: https://orcid.org/0009-0003-5073-1522)
- Bartosz Perkowski (ORCID: https://orcid.org/0000-0001-5407-5313)
- Iwona Baranowska (ORCID: https://orcid.org/0000-0002-8680-4442)
- Katsiaryna Marhelava (ORCID: https://orcid.org/0000-0002-9422-5969)
- Klaudyna Fidyt (ORCID: https://orcid.org/0000-0003-0568-4950)
- Marta Krawczyk (ORCID: https://orcid.org/0000-0001-9487-1744)
- Małgorzata Firczuk (ORCID: https://orcid.org/0000-0002-1719-5233)
- Magdalena Winiarska (ORCID: https://orcid.org/0000-0001-5605-3329)
- Narcís Fernández‐Fuentes (ORCID: https://orcid.org/0000-0002-6421-1080)
- Else Marit Inderberg
- Thibault Leray
- Natalia Czerwik
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Oslo University Hospital (NO)
- Hospital Sant Joan de Déu Barcelona (ES)
- Medical University of Silesia (PL)
- University of Oslo (NO)
- Medical University of Warsaw (PL)
- Instituto de Salud Carlos III (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Instytut Hematologii i Transfuzjologi (PL)
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences (PL)
- Mossakowski Medical Research Institute, Polish Academy of Sciences (PL)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universitat de Barcelona (ES)
- Polish Academy of Sciences (PL)
Publication Details
- Journal
- Leukemia
- Published
- 2025-04-05
- DOI
- https://doi.org/10.1038/s41375-025-02580-z
- Citations
- 3
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- European Commission
- Uniwersytet Łódzki
- H2020 Marie Skłodowska-Curie Actions
- HORIZON EUROPE Marie Sklodowska-Curie Actions